Furoxanthone derivatives useful as diuretics

ABSTRACT

Xanthone derivatives of the formula (I): ##STR1## (wherein W, X, Y and Z which may be the same or different represent a hydrogen atom, a halogen atom or a lower alkyl group having 1 to 4 carbon atoms; A is hydrogen atom or together with Z forms a --CH 2  -- group which binds to a phenyl carbon adjacent the phenyl carbon to which the oxygen of the group ##STR2## is attached to form a cyclic methylene chain; B is a hydroxymethyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, or a carboxyl group, provided that W is neither a hydrogen atom nor a 7-position methyl group when X, Y and Z are each a hydrogen atom, and A is a hydrogen atom and B is a carboxyl group or a lower alkoxycarbonyl group), as well as non-toxic salts thereof when B is a carboxyl group, and a process for preparing the same are disclosed. 
     The compounds of formula (I) in accordance with the present invention are useful as diuretics having uricosuric activity and can be used in the treatment of edema or hypertension.

The present invention relates to xanthone derivatives of the formula(I): ##STR3## (wherein W, X, Y and Z which may be the same or differentrepresent a hydrogen atom, a halogen atom or a lower alkyl group having1 to 4 carbon atoms; A is a hydrogen atom or together with Z forms a--CH₂ -- group which binds to a phenyl carbon adjacent the phenyl carbonto which the oxygen of the group ##STR4## is attached to form a cyclicmethylene chain; B is a hydroxymethyl group, a lower alkoxycarbonylgroup having 1 to 4 carbon atoms, or a carboxyl group, provided that Wis neither a hydrogen atom nor a 7-position methyl group when X, Y and Zare each a hydrogen atom, and A is a hydrogen atom and B is a carboxylgroup or a lower alkoxycarbonyl group), as well as non-toxic saltsthereof when B is a carboxyl group.

The compounds of formula (I) in accordance with the present inventionare useful as diuretics having uricosuric activity and can be used inthe treatment of edema or hypertension.

Diuretics known to have uricosuric activity like the compounds of thepresent invention are phenoxyacetic acids typified by thienylic acid(U.S. Pat. No. 3,758,506).

Conventional diuretic hypotensive agents are extensively used as drugsof the first choice in the treatment of hypertension, but they have ahigh potential of causing hyperuricemia as a side effect. Furthermore,hypertension is often complicated by hyperuricemia and many cases ofhyperuricemia are belived to be caused by disorders in the excretion ofuric acid. Under these circumstances, there exists a strong need inmedical fields for the development of diuretics having uricosuricactivity. As already mentioned, thienylic acid is known to be apotential diuretic having uricosuric activity, but is yet to becommercialized because of the high possibility of causing liverdisorders as a side effect.

As a result of various studies made to overcome these disadvantages, thepresent inventors have found that the xanthone derivatives of formula(I) have both uricosuric and diuretic activities and yet cause minimumside effects on the liver. The present invention has been accomplishedon the basis of this finding.

The xanthone derivatives of formula (I) in accordance with the presentinvention are specifically classified as the compounds of formula (II)and furoxanthones of formula (III): ##STR5## (wherein W, X, Y, Z and Bmean the same as defined for formula (I), provided that W is neither ahydrogen atom nor a 7-position methyl group when X, Y, Z are each ahydrogen atom and B is a carboxyl group or a lower alkoxycarbonylgroup); ##STR6## (wherein W, X, Y and B mean the same as defined above).

In the xanthone derivatives of formulas (I), (II) and (III), the halogenatom is fluorine, chlorine, bromine or iodine, and the lower alkyl groupis a straight-chained or branched alkyl group having 1 to 4 carbonatoms). When B is a carboxyl group, the derivatives may form salts withbases. Illustrative salts include alkali metal salts, alkaline earthmetal salts and substituted or unsubstituted amine salts. Specificexamples of such salts are sodium salts, calcium salts, magnesium salts,ammonium salts, lower alkylamine salts and ethanolamine salts. Thesesalts may be readily formed by conventional methods

The compounds of formual (I) in accordance with the present inventionare novel. The compounds of formula (II) may be prepared by reactingcompounds of formula (IV): ##STR7## (wherein W, X, Y and Z mean the sameas defined above) with compounds of the formula: L--CH₂ --B (wherein Bis the same as defined above, and L is a halogen atom, a hydroxyl groupor an acyloxy group as a leaving group). The reaction is preferablyperformed in the presence of a base in an inert solvent. Examples of theinert solvent include ethers, alcohols, hydrocarbons, aromatichydrocarbons, water, and aprotic polar solvents such asN,N-dimethylformamide and dimethyl sulfoxide. Illustrative bases arehydrides, alkoxides, hydroxides and carbonates of alkali metals andorganic bases. More specific examples include sodium hydride, sodiummethoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate and triethylamine. The reactiontemperature is appropriately selected from the range of 0° C. to about150° C.

The xanthone derivatives of formula (II) wherein B is a carboxyl groupmay also be prepared from corresponding compounds wherein B is a loweralkoxycarbonyl group by conventional methods, for example, by thehydrolysis of them using alkaline hydroxides.

Specific examples of the furoxanthone derivatives of formula (III) inaccordance with the present invention are 5-oxo-5H-furo[3,2-b]xanthenesand 6-oxo-6H-furo[2,3-c]xanthenes. Compounds of formula (IIIa)represented by the following formula are included within the scope ofthe compounds of the present invention. ##STR8## (wherein X, Y and W arethe same as defined above) They may be prepared by reacting peracidswith compounds of formula (V): ##STR9## (wherein X, Y and W mean thesame as defined above, provided that the hydroxyl and allyl groups aresubstituted at vicinal positions).

By subjecting these compounds of formula (IIIa) to oxidation, compoundsof formual (IIIb) which are also within the scope of the invention areobtained: ##STR10## (wherein X, Y and W are the same as defined above).

The compounds of formula (III) wherein B is a lower alkoxycarbonyl groupmay be prepared by esterifying the compounds of formula (IIIb) inaccordance with conventional methods. In these productions, the reactionis carried out in an inert solvent such as ethers and hydrocarbons. Thereaction temperature is properly selected from the range of 0° C. toabout 150° C. Organic peracids such as peracetic acid, perbenzoic acidand m-chloroperbenzoic acid may be used as peracids in the step ofproducing the compounds of formula (IIIa) from the compounds of formula(V). The oxidative reaction by which the compounds of formual (IIIa) areconverted to the compounds of formula (IIIb) may be performed by aconventional technique, such as by using oxides of manganese, chromium,etc. The compounds of formula (V) may be prepared by subjecting thecorresponding allyl aryl ethers to the Claisen rearrangement reaction.

Pharmacological Activities of the Compounds

The diuretic and uricosuric activities of the compounds of the presentinvention were confirmed by the following experiment.

Method:

Seven-week old Wistar-Imamichi rats that had been starved for 24 hourswere divided in groups of four or five heads so that the animals of eachgroup would excrete almost the same amount of urine. After forcedurination, the rats were orally administered the test compounds thatwere suspended in physiological saline containing 3% gum arabic in adose volume of 25 ml per kg of the body weight. The suspensions wereadministered typically in an amount of 100 mg/kg. Control rats weregiven only physiological saline containing 3% gum arabic. The animalswere housed in separate metabolic cages and the urine excreted from eachanimal was collected over a period of 6 hours following theadministration of the test compounds or physiological saline aftercomplete starvation. The urine volume was directly read on a measuringcylinder after forced urination thereinto, and the amount of urine perkg of the body weight was calculated. The amount of uric acid excretedin the urine was determined by the uricase-catalase method.

Results:

As is apparent from the following table, the compounds of the presentinvention exhibited significant levels of diuretic and uricosuricactivities, which were found to be long-lasting and dose-dependent. Thecompound numbers given in the table are keyed to the specific Examplesshown later in this specification.

                  TABLE                                                           ______________________________________                                                 Amount of urine                                                                            Amount of uric acid                                     Test compound                                                                            ml/kg     %        ml/kg   %                                       ______________________________________                                        Control group                                                                            17.7 ± 3.9                                                                           100      3.44 ± 0.57                                                                        100                                     Compound 13                                                                              35.4 ± 7.6                                                                           199.5.sup.c                                                                            5.11 ± 1.00                                                                        148.6.sup.c                             Control group                                                                            16.7 ± 6.9                                                                           100      3.05 ± 0.48                                                                        100                                     Compound 21                                                                              31.8 ± 6.6                                                                           190.8.sup.c                                                                            3.86 ± 0.61                                                                        126.3.sup.b                             Control group                                                                            14.7 ± 1.8                                                                           100      2.38 ± 0.23                                                                        100                                     Compound 23                                                                              36.9 ± 3.3                                                                           250.3.sup.c                                                                            3.13 ± 0.22                                                                        131.7.sup.a                             Control group                                                                            18.1 ± 2.1                                                                           100      3.43 ± 0.20                                                                        100                                     Compound 35                                                                              49.7 ± 2.0                                                                           275.0.sup.c                                                                            4.30 ± 0.22                                                                        125.2.sup.a                             ______________________________________                                         .sup.a : P < 0.05, .sup.b : P < 0.01, .sup.C : P < 0.001                 

The following examples are provided for further illustrating the claimedcompounds but are not to be construed as limiting the invention.

EXAMPLE 1

A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8g of potassium carbonate, 3.3 g of ethyl bromoacetate and 40 ml ofN,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. Aftercooling the mixture, water was added thereto and the resulting crystalwas recovered by filtration, washed with water and dried.Recrystallization from ethanol gave 3.4 g of ethyl4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of thisester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxedfor 30 minutes. After cooling, the mixture was rendered acidic withconcentrated hydrochloric acid and the resulting crystal was recoveredby filtration and dried. Recrystallization from DMF gave 2.5 g of4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.

This compound exhibited a mass spectrum having a molecular ion peak atm/e 322.

EXAMPLE 2

A mixture of 1.2 g of 4-chloro-3-hydroxy-9-oxo-9H-xanthene, 1.7 g ofpotassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMF wasstirred at 60°-70° C. for 3 hours. After cooling the mixture, water wasadded and the resulting crystal was recovered by filtration, washed withwater and dried. Recrystallization from ethanol gave 1.1 g of ethyl4-chloro-9-oxo-9H-xanthene-3-yloxyacetate. m.p. 183°-185° C.

A mixture of this ester (0.9 g), sodium hydroxide (0.7 g) and water (40ml) was refluxed for 1 hour. After cooling, the mixture was renderedacidic with hydrochloric acid and the solid crystal was recovered byfiltration, washed with water and dried. Recrystallization from ethanolgave 0.7 g of 4-chloro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p.280°-281° C.

This compound exhibited a mass spectrum having a molecular ion peak atm/e 304.

EXAMPLE 3

A mixture of 1.0 g of 3-hydroxy-4-methyl-9-oxo-9H-xanthene, 1.5 g ofpotassium carbonate, 1.8 g of ethyl bromoacetate and 20 ml of DMF wasagitated at 60°-70° C. for 2 hours. After cooling the mixture, 2 g ofsodium hydroxide and 40 ml of water were added, and the resultingmixture was stirred at 90°-100° C. for 30 minutes. After cooling, themixture was rendered acidic with hydrochloric acid and the solid crystalwas recovered by filtration, washed with water and dried.Recrystallization from ethanol gave 1.0 g of4-methyl-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 244°-247° C. Thiscompound gave a mass spectrum having a molecular ion peak at m/e 284.

EXAMPLE b 4

A mixture of 1.8 g of 8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 3.2 g ofpotassium carbonate, 3.7 g of ethyl bromoacetate and 100 ml of DMF wasstirred at 60°-70° C. for 4 hours. After cooling the mixture, 5 g ofsodium hydroxide and 100 ml of water were added, and the resultingmixture was stirred at 90°-100° C. for 30 minutes. After cooling, themixture was rendered acidic with hydrochloric acid and the solid crystalwas recovered by filtration, washed with water and dried.Recrystallization from ethanol gave 2.0 g of8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 180°-183° C. Thiscompound showed a mass spectrum having a molecular ion peak at m/e 288.

EXAMPLE 5

A mixture of 1.5 g of 8-fluoro-3-hydroxy-4-methyl9-oxo-9H-xanthene, 3.0g of potassium carbonate, 3.6 g of ethyl bromoacetate and 40 ml of DMFwas stirred at 60°-70° C. for 2 hours. After cooling the mixture, sodiumhydroxide (3 g) and water (40 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 1.4 g of 8-fluoro-4-methyl-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 259°-261° C. This compound showed a mass spectrum having amolecular ion peak at m/e 302.

EXAMPLE 6

A mixture of 1.3 g of 2-chloro-8-fluoro-3-hydroxy9-oxo-9H-xanthene, 1.7g of potassium carbonate, 2.1 g of ethyl bromoacetate and 30 ml of DMFwas stirred at 60°-65° C. for 3 hours. After cooling the mixture, 2 g ofsodium hydroxide and 100 ml of water were added and the resultingmixture was stirred at 90 °-100° C. for 30 minutes. After cooling, themixture was rendered acidic with hydrochloric acid and the solid crystalwas recovered by filtration, washed with water and dried.Recrystallization from DMF gave 1.0 g of2-chloro-8-fluoro-9-oxo-9H-xanthene-3yloxyacetic acid. m.p. 239°-242° C.This compound gave a mass spectrum having a molecular ion peak at m/e322.

EXAMPLE 7

A mixture of 2.6 g of 3-chloro-8-fluoro-2-hydroxy-9-ono-9H-xanthene, 3.4g of potassium carbonate, 4.2 g of ethyl bromoacetate and 60 ml of DMFwas stirred at 60°-65° C. for 5 hours. After cooling the mixture, 4 g ofsodium hydroxide and 100 ml of water were added and the resultingmixture was stirred at 90°-100° C. for 30 minutes. After cooling, themixture was rendered acidic with hydrochloric acid and the solid crystalwas recovered by filtration, washed with water and dried.Recrystallization from ethanol gave 1.2 g of3-chloro-8-fluoro-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 242°-245°C. This compound exhibited a mass spectrum having a molecular ion peakat m/e 322.

EXAMPLE 8

A mixture of 4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.8 g), potassiumcarbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) wasstirred at 60°-65° C. for 6.5 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 2.4 g of 4,8-dichloro-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 270°-271° C. This compound showed a mass spectrum having amolecular ion peak at m/e 338.

EXAMPLE 9

A mixture of 4,6-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassiumcarbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) wasstirred at 60°-65° C. for 4 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 1.5 g of 4,6-dichloro-9-oxo9H-xanthene-3-yloxyacetic acid.m.p. 270° C. This compound gave a mass spectrum having a molecular ionpeak at m/e 338.

EXAMPLE 10

A mixture of 4-bromo-8-fluoro-2-hydroxy-9-oxo-9H-xanthene (1.5 g),potassium carbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml)was stirred at 60°-65° C. for 4 hours. After cooling the mixture, sodiumhydroxide (2 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 1.2 g of4-bromo-8-fluoro-9-oxo-9H-xanthene-2-yloxyacetic acid. m.p. 220°-223° C.This compound gave a mass spectrum having a molecular ion peak at m/e366.

EXAMPLE 11

A mixture of 4,7-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassiumcarbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) wasstirred at 60°-65° C. for 4 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 1.3 g of 4,7-dichloro-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 262°-263° C. This compound gave a mass spectrum having amolecular ion peak at m/e 338.

EXAMPLE 12

A mixture of 4,5-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassiumcarbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) wasstirred at 60°-65° C. for 4 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 1.5 g of 4,5-dichloro-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 283°-286° C. This compound gave a mass spectrum having amolecular ion peak at m/e 338.

EXAMPLE 13

To a mixture of 4-chlororesorcinol dimethyl ether (14.2 g),2-fluorobenzoyl chloride (13.0 g) and 1,2-dichloroethane (200 ml) wasadded 11 g of aluminum chloride in small portions with ice-cooling andstirred. The agitation was continued at room temperature for 2 hours.After refluxing for 1 hour, the mixture was poured into iced water andextracted with ether. After washing with water and drying, the solventwas distilled off. To the residue, 32 g of 28% sodium methoxide (inmethanol) and 300 ml of ethanol were added and the mixture was refluxedfor 1 hour. After cooling the mixture, 200 ml of water was added and thesolid crystal was recovered by filtration, washed with water and dried.The resulting crystal was added to a heated (185°-195° C.) pyridinehydrochloride and the mixture was stirred at that temperature for 2hours. After cooling the mixture, water was added and the solid crystalwas recovered by filtration, washed with water and dried. The resultingcrystal was added into a mixture of potassium carbonate (22.6 g), ethylbromoacetate (27.4 g) and DMF (400 ml) and the resulting mixture wasstirred at 65°-75° C. for 2 hours. After cooling the mixture, sodiumhydroxide (40 g) and water (400 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 1 hour. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 19 g of 2-chloro-9-oxo-9H-xanthene-3-yloxyacetic acid.m.p. 248°-249° C. This compound gave a mass spectrum having a molecularion peak at m/e 304.

EXAMPLE 14

A mixture of 3-chloro-2-hydroxy-9-oxo-9H-xanthene (1.5 g), potassiumcarbonate (2.5 g), ethyl bromoacetate (3.1 g) and DMF (40 ml) wasstirred at 65°-75° C. for 2 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 1.5 g of 3-chloro-9-oxo9H-xanthene-2-yloxyacetic acid.m.p. 237°-238° C. This compound showed a mass spectrum having amolecular ion peak at m/e 304.

EXAMPLE 15

A mixture of 4-bromo-2-hydroxy-9-oxo-9H-xanthene (2.0 g), potassiumcarbonate (1.9 g), ethyl bromoacetate (2.3 g) and DMF (20 ml) wasstirred at 60°-70° C. for 1.5 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (40 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 1.8 g of 4-bromo-9-oxo-9H-xanthene-2-yloxyacetic acid.m.p. 219°-221° C. This compound exhibited a mass spectrum having amolecular ion peak at m/e 348.

EXAMPLE 16

A mixture of 1-chloro-3-hydroxy-9-oxo-9H-xanthene (1.0 g), potassiumcarbonate (1.1 g), ethyl bromoacetate (1.4 g) and DMF (20 ml) wasstirred at 60°-70° C. for 5 hours. After cooling the mixture, sodiumhydroxide (2 g) and water (50 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 0.8 g of 1-chloro-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 231°-233° C. This compound showed a mass spectrum having amolecular ion peak at m/e 304.

EXAMPLE 17

A mixture of 1,2-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassiumcarbonate (2.0 g), ethyl bromoacetate (2.4 g) and DMF (40 ml) wasstirred at 60°-70° C. for 1.5 hours. After cooling the mixture, sodiumhydroxide (2 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 30 minutes. After cooling, the mixturewas rendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 1.7 g of 1.2-dichloro-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 288°-290° C. This compound showed a mass spectrum having amolecular ion peak at m/e 338.

EXAMPLE 18

A mixture of 2-hydroxy-3-methyl-9-oxo-9H-xanthene (1.1 g), potassiumcarbonate (1.4 g), ethyl bromoacetate (1.7 g) and DMF (20 ml) wasstirred at 60°-70° C. for 3 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 1 hour. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 1.3 g of 3-methyl-9-oxo-9H-xanthene-2-yloxyacetic acid.m.p. 225°-227° C. This compound showed a mass spectrum having amolecular ion peak at m/e 284.

EXAMPLE 19

A mixture of 3-hydroxy-1-methyl-9-oxo-9H-xanthene (5.0 g), potassiumcarbonate (6.0 g), ethyl bromoacetate (7.0 g) and DMF (100 ml) wasstirred at 60°-70° C. for 5 hours. After cooling the mixture, sodiumhydroxide (10 g) and water (200 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 1 hour. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 5.0 g of 1-methyl-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 189°-190° C. This compound exhibited a mass spectrum having amolecular ion peak at m/e 284.

EXAMPLE 20

A mixture of 2-chloro-3-hydroxy-1-methyl-9-oxo-9H-xanthene (1.3 g),potassium carbonate (1.4 g), ethyl bromoacetate (1.7 g) and DMF (20 ml)was stirred at 60°-70° C. for 5 hours. After cooling the mixture, sodiumhydroxide (4 g) and water (100 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 1 hour. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom DMF gave 0.9 g of 2-chloro-1-methyl-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 275°-278° C. This compound showed a mass spectrum having amolecular ion peak at m/e 318.

EXAMPLE 21

A mixture of 2-bromo-3-hydroxy-9-oxo-9H-xanthene (5.0 g), potassiumcarbonate (7.1 g), ethyl bromoacetate (8.6 g) and DMF (80 ml) wasstirred at 55°-65° C. for 5 hours. After cooling the mixture, sodiumhydroxide (10 g) and water (250 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 2 hours. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 3.0 g of 2-bromoto-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 227°-230° C. This compound showed a mass spectrum having amolecular ion peak at m/e 348.

EXAMPLE 22

A mixture of 2,4-dichloro-3-hydroxy-9-oxo-9H-xanthene (7.5 g), potassiumcarbonate (7.5 g), ethyl bromoacetate (9.0 g) and DMF (100 ml) wasstirred at 55°-65° C. for 3 hours. After cooling the mixture, sodiumhydroxide (20 g) and water (250 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 1 hour. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 4.0 g of 2,4-dichloro-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 225°-228° C. This compound gave a mass spectrum having amolecular ion peak at m/e 338.

EXAMPLE 23

A mixture of 3-hydroxy-2-methyl-9-oxo-9H-xanthene (1.8 g), potassiumcarbonate (2.2 g), ethyl bromoacetate (2.7 g) and DMF (40 ml) wasstirred at 60°-70° C. for 2 hours. After cooling the mixture, sodiumhydroxide (3.2 g) and water (40 ml) were added and the resulting mixturewas stirred at 90°-100° C. for 1 hour. After cooling, the mixture wasrendered acidic with hydrochloric acid and the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 1.8 g of 2-methyl-9-oxo-9H-xanthene-3-yloxyaceticacid. m.p. 236°-238° C. This compound showed a mass spectrum having amolecular ion peak at m/e 284.

EXAMPLE 24

A mixture of 2-chloro-3-hydroxy-9-oxo-9H-xanthene (8.0 g), potassiumcarbonate (13 g), 2-bromoethanol (12 g) and DMF (200 ml) was stirred at45°-55° C. for 3 hours. After distilling off the solvent under vacuum,water was added to the residue and the solid crystal was recovered byfiltration, washed with water and dried. Recrystallization from a mixedsolvent of DMF and water gave 6.0 g of2-chloro-3-(2-hydroxyethoxy)-9-oxo-9H-xanthene. m.p. 153°-156° C. Thiscompound produced a mass spectrum having a molecular ion peak at m/e290.

EXAMPLE 25

To a mixture of 2-allyl-3-hydroxy-4-methyl-9-oxo-9H-xanthene (11 g) andchloroform (800 ml), 9.5 g of m-chloroperbenzoic acid was added and theresulting mixture was stirred at room temperature for 5 hours, followedby standing overnight. To the mixture, potassium carbonate (20 g) andwater (500 ml) were added and the resulting mixture was subjected toextraction with chloroform. The chloroform layer was dried and thesolvent was distilled off. The residue was recrystallized from ethanolto obtain 10 g of2,3-dihydro-2-hydroxymethyl-11-methyl-5-oxo-5H-furo[3,2-b]xanthene. m.p.242°-243° C. This compound gave a mass spectrum having a molecular ionpeak at m/e 282.

EXAMPLE 26

To an ice-cooled mixture of 16.1 of the2,3-dihydro-2-hydroxymethyl-11-methyl-5-oxo-5H-furo[3,2-b]xantheneobtained in Example 25 and 3,000 ml of acetone, a mixture of chromiumtrioxide (57 g), water (280 ml) and concentrated sulfuric acid (84 g)was added dropwise under agitation. The resulting mixture was left tostand overnight and filtered. The filtrate was evaporated to drynessunder vacuum. After addition of water, the solid crystal was recoveredby filtration, washed with water and dried. Recrystallization from amixed solvent of methanol and dichloromethane gave 11.1 g of2,3-dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid.m.p. 297°-299° C. This compound produced a mass spectrum having amolecular ion peak at m/e 296.

EXAMPLE 27

A mixture of 4-allyl-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (1.4 g),m-chloroperbenzoic acid (1.2 g) and chloroform (250 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight.After addition of potassium carbonate (2 g) and water (50 ml), themixture was extracted with chloroform. The chloroform layer was driedand the solvent was distilled off. The residue was recrystallized fromethanol to obtain 1.2 g of7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene. m.p.220°-221° C. This compound gave a mass spectrum having a molecular ionpeak at m/e 286.

EXAMPLE 28

To an ice-cooled mixture of 8.0 g of the7-fluoro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xantheneobtained in Example 27 and 1,000 ml of acetone, a mixture of chromiumtrioxide (14 g), water (80 ml) and concentrated sulfuric acid (24 g) wasadded dropwise under agitation. The resulting mixture was left to standovernight and filtered. The filtrate was evaporated to dryness undervacuum. After addition of water, the solid crystal was recovered byfiltration, washed with water and dried. Recrystallization fromN,N-dimethylformamide (DMF) gave 8.1 g of7-fluoro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid.m.p. 262°-265° C. This compound produced a mass spectrum having amolecular ion peak at m/e 300.

EXAMPLE 29

A mixture of 2-allyl-8-fluoro-3-hydroxy-4-methyl-9-oxo-9H-xanthene (9.0g), m-chloroperbenzoic acid (8.0 g) and chloroform (1,000 ml) wasstirred at room temperature for 5 hours and left to stand overnight. Tothe mixture, potassium carbonate (20 g) and water (500 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (1,000 ml) and to the stirred solution, a mixtureof chromium trioxide (21 g), water (120 ml) and concentrated sulfuricacid (36 g) was added dropwise at room temperature. After leaving it tostand overnight, the mixture was filtered and the filtrate wasevaporated to dryness under vacuum. After addition of water, the solidcrystal was recovered by filtration, washed with water and dried.Recrystallization from ethanol gave 5.0 g of6-fluoro-2,3-dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylicacid. m.p. 292°-295° C. This compound produced a mass spectrum having amolecular ion peak at m/e 314.

EXAMPLE 30

A mixture of 4-allyl-8-chloro-3-hydroxy-9-oxo-9H-xanthene (15 g),m-chloroperbenzoic acid (14 g) and chloroform (1,000 ml) was stirred atroom temperature for 5 hours and left to stand overnight. To themixture, potassium carbonate (20 g) and water (500 ml) were added andthe resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (2,000 ml) and, to the stirred solution, a mixtureof chromium trioxide (15 g), water (90 ml) and concentrated sulfuricacid (26 g) was added dropwise at room temperature. After standingovernight, the mixture was filtered and the filtrate was evaporated todryness under vacuum. After addition of water, the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 8.0 g of7-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid.m.p. 283°-286° C. This compound produced a mass spectrum having amolecular ion peak at m/e 316.

EXAMPLE 31

A mixture of 2-allyl-4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (14 g),m-chloroperbenzoic acid (11 g ) and chloroform (1,000 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (20 g) and water (500 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (2,000 ml) and to the stirred solution, a mixtureof chromium trioxide (17 g), water (100 ml) and concentrated sulfuricacid (30 g) was added dropwise at room temperature. After standingovernight, the mixture was filtered and the filtrate was evaporated todryness under vacuum. After addition of water, the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 5.0 g of6,11-dichloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylicacid. m.p. 291°-294° C. This compound showed a mass spectrum having amolecular ion peak at m/e 350.

EXAMPLE 32

A mixture of 4-allyl-3-hydroxy-9-oxo-9H-xanthene (10 g),m-chloroperbenzoic acid (21 g) and chloroform (1,000 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (40 g) and water (1,000 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (2,000 ml) and, to the stirred solution, a mixtureof chromium trioxide (9 g), water (40 ml) and concentrated sulfuric acid(15 g) was added dropwise at room temperature. After standing overnight,the mixture was filtered and the filtrate was evaporated to drynessunder vacuum. After addition of water, the solid crystal was recoveredby filtration, washed with water and dried. Recrystallization fromethanol gave 4 g of1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p.283°-286° C. This compound showed a mass spectrum having a molecular ionpeak at m/e 282.

EXAMPLE 33

A mixture of 2-allyl-4-chloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g),m-chloroperbenzoic acid (3.6 g) and chloroform (100 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (8 g) and water (200 ml) were added andthe resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (400 ml) and to the stirred solution, a mixture ofchromium trioxide (1.7 g), water (10 ml) and concentrated sulfuric acid(3 g) was added dropwise at room temperature. After standing overnight,the mixture was filtered and the filtrate was evaporated to drynessunder vacuum. After addition of water, the solid crystal was recoveredby filtration, washed with water and dried. Recrystallization fromethanol gave 0.9 g of11-chloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid.m.p. 290°-293° C. This compound exhibited a mass spectrum having amolecular ion peak at m/e 316.

EXAMPLE 34

A mixture of 2-allyl-4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (2.8g), m-chloroperbenzoic acid (4.7 g) and chloroform (100 ml) was stirredat room temperature for 5 hours and thereafter left to stand overnight.To the mixture, potassium carbonate (10 g) and water (200 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (500 ml) and, to the stirred solution, a mixture ofchromium trioxide (2.8 g), water (16 ml) and concentrated sulfuric acid(4.8 g) was added dropwise at room temperature. After standingovernight, the mixture was filtered and the filtrate was evaporated todryness under vacuum. After addition of water, the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 1.0 g of11-chloro-6-fluoro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylicacid. m.p. 300° C. This compound showed a mass spectrum having amolecular ion peak at m/e 334.

EXAMPLE 35

A mixture of 4-allyl-2-chloro-3-hydroxy-9-oxo-9H-xanthene (2.9 g),m-chloroperbenzoic acid (3.5 g) and chloroform (300 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (10 g) and water (200 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The obtained4-chloro-1,2-dihydro-2-hydroxymethyl-6-oxo-6H-furo[2,3-c]xanthene wasdissolved in acetone (300 ml) and, to the stirred solution, a mixture ofchromium trioxide (3.3 g), water (17 ml) and concentrated sulfuric acid(5 g) was added dropwise at room temperature. After standing overnight,to the mixture was added isopropanol (10 ml) and the resulting mixturewas filtered and the filtrate was evaporated to dryness under vacuum.After adding water, the solid crystal was recovered by filtration,washed with water and dried. Recrystallization from ethanol gave 1.7 gof 4-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid.m.p. 292°-295° C. This compound showed a mass spectrum having amolecular ion peak at m/e 316.

EXAMPLE 36

A mixture of 4-allyl-1-chloro-3-hydroxy-9-oxo-9H-xanthene (3.0 g),m-chloroperbenzoic acid (7.2 g) and chloroform (500 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (20 g) and water (400 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (300 ml) and, to the stirred solution, a mixture ofchromium trioxide (3.3 g), water (17 ml) and concentrated sulfuric acid(5 g) was added dropwise at room temperature. After standing overnight,the mixture was filtered and the filtrate was evaporated to drynessunder vacuum. After addition of water, the solid crystal was recoveredby filtration, washed with water and dried. Recrystallization fromethanol gave 1.6 g of5-chloro-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carbolyxic acid.m.p. 255°-258° C. This compound showed a mass spectrum having amolecular ion peak at m/e 316.

EXAMPLE 37

A mixture of 4-allyl-3-hydroxy-1-methyl-9-oxo-9H-xanthene (3.0 g),m-chloroperbenzoic acid (8 g) and chloroform (500 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (20 g) and water (400 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (500 ml) and, to the stirred solution, a mixture ofchromium trioxide (5.5 g), water (25 ml) and concentrated sulfuric acid(8.5 g) was added dropwise at room temperature. After standingovernight, the mixture was filtered and the filtrate was evaporated todryness under vacuum. After addition of water, the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom ethanol gave 1.5 g of1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid.m.p. 231°-234° C. This compound exhibited a mass spectrum having amolecular ion peak at m/e 298.

EXAMPLE 38

A mixture of 4-allyl-2-chloro-3-hydroxy-1-methyl-9-oxo-9H-xanthene (2.8g), m-chloroperbenzoic acid (6.4 g) and chloroform (300 ml) was stirredat room temperature for 5 hours and thereafter left to stand overnight.To the mixture, potassium carbonate (20 g) and water (400 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (500 ml) and, to the stirred solution, a mixture ofchromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8g) was added dropwise at room temperature. After standing overnight, themixture was filtered and the filtrate was evaporated to dryness undervacuum. After addition of water, the solid crystal was recovered byfiltration, washed with water and dried. Recrystallization from ethanolgave 1.6 g of4-chloro-1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylicacid. m.p. 284°-287° C. This compound showed a mass spectrum having amolecualr ion peak at m/e 330.

EXAMPLE 39

A mixture of 4-allyl-2-bromo-3-hydroxy-9-oxo-9H-xanthene (3.0 g),m-chloroperbenzoic acid (10 g) and chloroform (250 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, potassium carbonate (20 g) and water (400 ml) were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent distilled off. The residue was dissolvedin acetone (300 ml) and, to the stirred solution, a mixture of chromiumtrioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) wasadded dropwise at room temperature. After standing overnight, themixture was filtered and the filtrate was evaporated to dryness undervacuum. After addition of water, the solid crystal was recovered byfiltration, washed with water and dried. Recrystallization from ethanolgave 1.5 g of4-bromo-1,2-dihydro-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p.283°-286° C. This compound showed a mass spectrum having a molecular ionpeak at m/e 360.

EXAMPLE 40

A mixture of 4-allyl-3-hydroxy-2-methyl-9-oxo-9H-xanthene (12 g),m-chloroperbenzoic acid (12 g) and chloroform (700 ml) was stirred atroom temperature for 5 hours and thereafter left to stand overnight. Tothe mixture, 20 g of potassium carbonate and 400 ml of water were addedand the resulting mixture was extracted with chloroform. The chloroformlayer was dried and the solvent was distilled off. The residue wasdissolved in acetone (2,000 ml) and, to the stirred solution, a mixtureof chromium trioxide (34 g), water (70 ml) and concentrated sulfuricacid (30 ml) was added dropwise at room temperature. After standingovernight, the mixture was filtered and the filtrate was evaporated todryness under vacuum. After addition of water, the solid crystal wasrecovered by filtration, washed with water and dried. Recrystallizationfrom a mixed solvent of ethanol and DMF gave 8.7 g of1,2-dihydro-4-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid.m.p. 292°-295° C. This compound produced a mass spectrum having amolecular ion peak at m/e 296.

What is claimed is:
 1. A furoxanthone derivative of the formula:##STR11## wherein W, X and Y which are the same or different represent ahydrogen atom, a halogen atom or a lower alkyl group having 1 to 4carbon atoms; B is a hydroxymethyl group, a lower alkoxycarbonyl grouphaving up to 4 carbon atoms or a carboxyl group, and the ringrepresented by A is constructed by five atoms, or a non-toxic salt ofsaid derivative when B is a carboxyl group.
 2. A compound according toclaim 1, which is represented by the formula: ##STR12## wherein W, X, Yand B mean the same as defined in claim
 1. 3. A compound according toclaim 1, which is represented by the formula: ##STR13## wherein W, X, Yand B mean the same as defined in claim 1.